Targeting mutant huntingtin for the development of disease-modifying therapy

Drug Discovery Today

Volumn 17, Issue 21-22, 2012, Pages 1217-1223

  Appl, Thomas ^a   Kaltenbach, Linda ^b   Lo, Donald C ^b   Terstappen, Georg C ^a  

^a ABBOTT GMBH AND CO KG   (Germany)

^b DUKE UNIVERSITY MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

APOLIPOPROTEIN E; ATAXIN 1; CHOLESTEROL; COMPLEMENTARY DNA; HISTONE ACETYLTRANSFERASE; HISTONE DEACETYLASE; HISTONE DEACETYLASE 1; HUNTINGTIN; LEUCINE RICH REPEAT KINASE 2; POLYGLUTAMINE; VORINOSTAT;

AMYOTROPHIC LATERAL SCLEROSIS; BRAIN REGION; BRONCHIOLITIS OBLITERANS; CORPUS STRIATUM; FUNCTIONAL DISEASE; GENETIC TRANSCRIPTION; HUMAN; HUNTINGTON CHOREA; NERVE DEGENERATION; NEUROPROTECTION; NEUROTOXICITY; NONHUMAN; PALMITOYLATION; PARKINSON DISEASE; PATHOGENESIS; PATHOGENICITY; PROTEIN AGGREGATION; PROTEIN CLEAVAGE; PROTEIN FOLDING; PROTEIN PHOSPHORYLATION; PROTEIN PROCESSING; RESPIRATORY SYNCYTIAL PNEUMOVIRUS; REVIEW; RNA INTERFERENCE; SINGLE NUCLEOTIDE POLYMORPHISM; SUMOYLATION; UBIQUITINATION;

ANIMALS; BRAIN; COGNITION DISORDERS; DRUG DESIGN; HUMANS; HUNTINGTON DISEASE; MOLECULAR TARGETED THERAPY; MUTATION; NERVE TISSUE PROTEINS; PROTEIN FOLDING;

EID: 84868087531     PISSN: 13596446     EISSN: 18785832     Source Type: Journal    
DOI: 10.1016/j.drudis.2012.06.017     Document Type: Review

References (131)

1. F.O. Walker Huntington's disease Lancet 369 2007 218 228 (Pubitemid 46107685)
2. Huntington's Disease Collaborative Research Group A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group Cell 72 1993 971 983
3. R.J. Morse Pharmaceutical development for Huntington's disease D.C. Lo, R.E. Hughes, Neurobiology of Huntington's Disease: Applications to Drug Discovery 2011 CRC Press 197 224
4. M. DiFiglia Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain Science 277 1997 1990 1993
5. S.W. Davies Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation Cell 90 1997 537 548 (Pubitemid 27347243)
6. J.K. Cooper Truncated N-terminal fragments of huntingtin with expanded glutamine repeats form nuclear and cytoplasmic aggregates in cell culture Hum. Mol. Genet. 7 1998 783 790 (Pubitemid 28221240)
7. M. Arrasate, and S. Finkbeiner Protein aggregates in Huntington's disease Exp. Neurol. 2011 10.1016/j.expneurol.2011.12.013
8. C.A. Ross, and S.J. Tabrizi Huntington's disease: from molecular pathogenesis to clinical treatment Lancet Neurol. 10 2011 83 98
9. W. Fecke Small molecule drug discovery for Huntington's disease Drug Discov. Today 14 2009 453 464
10. C. Zuccato Molecular mechanisms and potential therapeutical targets in Huntington's disease Physiol. Rev. 90 2010 905 981
11. C.D. Johnson, and B.L. Davidson Huntington's disease: progress toward effective disease-modifying treatments and a cure Hum. Mol. Genet. 19 2010 98 102
12. S. Frank Tetrabenazine: the first approved drug for the treatment of chorea in US patients with Huntington disease Neuropsychiatr. Dis. Treat. 6 2010 657 665
13. R.M. Bonelli, and P. Hofmann A systematic review of the treatment studies in Huntington's disease since 1990 Exp. Opin. Pharmacother. 8 2007 141 153 (Pubitemid 46206617)
14. C.S. Venuto Pharmacologic approaches to the treatment of Huntington's disease Mov. Disord. 27 2012 31 41
15. A.J. Larner Cholinesterase inhibitors: beyond Alzheimer's disease Exp. Rev. Neurother. 10 2010 1699 1705
16. E. Gonzalez-Couto Huntington's disease: from experimental models to interaction networks, patho-pathway construction and disease hypothesis BMC Syst. Biol. 1 Suppl. 1 2007 45
17. L.S. Kaltenbach Huntingtin interacting proteins are genetic modifiers of neurodegeneration PLoS Genet. 3 2007 e82
18. S.J. Dixon, and B.R. Stockwell Identifying druggable disease-modifying gene products Curr. Opin Chem. Biol. 13 2009 549 555
19. A.L. Hopkins, and C.R. Groom The druggable genome Nat. Rev. Drug Discov. 1 2002 727 730 (Pubitemid 37361545)
20. S.P. Kwak Target validation for Huntington's disease D.C. Lo, R.E. Hughes, Neurobiology of Huntington's Disease: Applications to Drug Discovery 2011
21. N.M. Bonini, and A.R. La Spada Silencing polyglutamine degeneration with RNAi Neuron 48 2005 715 718 (Pubitemid 41759422)
22. V. Drouet Sustained effects of nonallele-specific Huntingtin silencing Ann. Neurol. 65 2009 276 285
23. J. Hu Allele-specific silencing of mutant huntingtin and ataxin-3 genes by targeting expanded CAG repeats in mRNAs Nat. Biotechnol. 27 2009 478 484
24. E.L. Pfister Five siRNAs targeting three SNPs may provide therapy for three-quarters of Huntington's disease patients Curr. Biol. 19 2009 774 778
25. P.H. van Bilsen Identification and allele-specific silencing of the mutant huntingtin allele in Huntington's disease patient-derived fibroblasts Hum. Gene Ther. 19 2008 710 719
26. R. Grondin Six-month partial suppression of Huntingtin is well tolerated in the adult rhesus striatum Brain 135 2012 1197 1209
27. S.Q. Harper RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model Proc. Natl. Acad. Sci. U. S. A. 102 2005 5820 5825 (Pubitemid 40559643)
28. E. Rodriguez-Lebron Intrastriatal rAAV-mediated delivery of anti-huntingtin shRNAs induces partial reversal of disease progression in R6/1 Huntington's disease transgenic mice Mol. Ther. 12 2005 618 633 (Pubitemid 41350143)
29. A. Akinc Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms Mol. Ther. 18 2010 1357 1364
30. S.Q. Harper Progress and challenges in RNA interference therapy for Huntington disease Arch. Neurol. 66 2009 933 938
31. A.A. Seyhan RNAi: a potential new class of therapeutic for human genetic disease Hum. Genet. 130 2011 583 605
32. D.W. Sah, and N. Aronin Oligonucleotide therapeutic approaches for Huntington disease J. Clin. Invest. 121 2011 500 507
33. Y.E. Choonara Trends in the molecular pathogenesis and clinical therapeutics of common neurodegenerative disorders Int. J. Mol. Sci. 10 2009 2510 2557
34. Y. Uno High-density lipoprotein facilitates in vivo delivery of alpha-tocopherol-conjugated short-interfering RNA to the brain Hum. Gene Ther. 22 2011 711 719
35. H. Xia RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia Nat. Med. 10 2004 816 820 (Pubitemid 39070854)
36. T. Zu Recovery from polyglutamine-induced neurodegeneration in conditional SCA1 transgenic mice J. Neurosci. 24 2004 8853 8861 (Pubitemid 39362981)
37. G.S. Ralph Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends survival in an ALS model Nat. Med. 11 2005 429 433 (Pubitemid 40562334)
38. T. Kubodera In vivo application of an RNAi strategy for the selective suppression of a mutant allele Hum. Gene Ther. 22 2011 27 34
39. L. de Ynigo-Mojado Efficient allele-specific targeting of LRRK2 R1441 mutations mediated by RNAi PLoS ONE 6 2011 e21352
40. M.E. Davis Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles Nature 464 2010 1067 1070
41. S.A. Leachman First-in-human mutation-targeted siRNA phase Ib trial of an inherited skin disorder Mol. Ther. 18 2010 442 446
42. M.R. Zamora RNA interference therapy in lung transplant patients infected with respiratory syncytial virus Am. J. Respir. Crit. Care Med. 183 2011 531 538
43. D. Castanotto, and J.J. Rossi The promises and pitfalls of RNA-interference-based therapeutics Nature 457 2009 426 433
44. R.P. Hickerson Development of quantitative molecular clinical end points for siRNA clinical trials J. Invest. Dermatol. 131 2011 1029 1036
45. J.K. Watts, and D.R. Corey Silencing disease genes in the laboratory and the clinic J. Pathol. 226 2012 365 379
46. R.A. Smith Antisense oligonucleotide therapy for neurodegenerative disease J. Clin. Invest. 116 2006 2290 2296 (Pubitemid 44162339)
47. P.N. Porensky A single administration of morpholino antisense oligomer rescues spinal muscular atrophy in mouse Hum. Mol. Genet. 21 2012 1625 1638
48. E.Y. Osman Bifunctional RNAs targeting the intronic splicing silencer N1 increase SMN levels and reduce disease severity in an animal model of spinal muscular atrophy Mol. Ther. 20 2012 119 126
49. J.B. Carroll Potent and selective antisense oligonucleotides targeting single-nucleotide polymorphisms in the Huntington disease gene/allele-specific silencing of mutant huntingtin Mol. Ther. 19 2011 2178 2185
50. K.T. Gagnon Antisense and antigene inhibition of gene expression by cell-permeable oligonucleotide-oligospermine conjugates J. Am. Chem. Soc. 133 2011 8404 8407
51. M.M. Evers Targeting several CAG expansion diseases by a single antisense oligonucleotide PLoS ONE 6 2011 e24308
52. A.L. Southwell Perturbation with intrabodies reveals that calpain cleavage is required for degradation of huntingtin exon 1 PLoS ONE 6 2011 e16676
53. D.W. Colby Potent inhibition of huntingtin aggregation and cytotoxicity by a disulfide bond-free single-domain intracellular antibody Proc. Natl Acad. Sci. U. S. A. 101 2004 17616 17621 (Pubitemid 40051935)
54. A. Snyder-Keller Early or late-stage anti-N-terminal Huntingtin intrabody gene therapy reduces pathological features in B6.HDR6/1 mice J. Neuropathol. Exp. Neurol. 69 2010 1078 1085
55. A.L. Southwell Intrabody gene therapy ameliorates motor, cognitive, and neuropathological symptoms in multiple mouse models of Huntington's disease J. Neurosci. 29 2009 13589 13602
56. A. Messer Developing intrabodies for the therapeutic suppression of neurodegenerative pathology Exp. Opin. Biol. Ther. 9 2009 1189 1197
57. R. Pul Antibody-based therapy in Alzheimer's disease Exp. Opin. Biol. Ther. 11 2011 343 357
58. S. Przedborski Can we reverse alpha-synuclein lesions? Mov. Disord. 26 2011 1618
59. M. Pennuto Post-translational modifications of expanded polyglutamine proteins: impact on neurotoxicity Hum. Mol. Genet. 18 2009 40 47
60. A. Crespo, and A. Fernandez Kinase packing defects as drug targets Drug Discov. Today 12 2007 917 923 (Pubitemid 350052679)
61. Y. Wang The role of post-translational modifications of huntingtin in the pathogenesis of Huntington's disease Neurosci. Bull. 26 2010 153 162
62. D.E. Ehrnhoefer Small changes, big impact: posttranslational modifications and function of huntingtin in Huntington disease Neuroscientist 17 2011 475 492
63. F.B. Young Putting proteins in their place: palmitoylation in Huntington disease and other neuropsychiatric diseases Prog. Neurobiol. 97 2012 220 238
64. J.S. Steffan SUMO modification of Huntingtin and Huntington's disease pathology Science 304 2004 100 104 (Pubitemid 38451465)
65. M. Drag, and G.S. Salvesen Emerging principles in protease-based drug discovery Nat. Rev. Drug Discov. 9 2010 690 701
66. C.M. Overall, and R.A. Dean Degradomics: systems biology of the protease web. Pleiotropic roles of MMPs in cancer Cancer Metastasis Rev. 25 2006 69 75 (Pubitemid 43723983)
67. J. Hu Matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases Nat. Rev. Drug Discov. 6 2007 480 498 (Pubitemid 47064570)
68. P.S. Vosler Calpain-mediated signaling mechanisms in neuronal injury and neurodegeneration Mol. Neurobiol. 38 2008 78 100
69. J.P. Miller Matrix metalloproteinases are modifiers of huntingtin proteolysis and toxicity in Huntington's disease Neuron 67 2010 199 212
70. M.B. Bevers, and R.W. Neumar Mechanistic role of calpains in postischemic neurodegeneration J. Cereb. Blood Flow Metab. 28 2008 655 673 (Pubitemid 351432797)
71. P. Majumder Increased caspase-2, calpain activations and decreased mitochondrial complex II activity in cells expressing exogenous huntingtin exon 1 containing CAG repeat in the pathogenic range Cell Mol. Neurobiol. 27 2007 1127 1145 (Pubitemid 351170078)
72. C.M. Cowan Polyglutamine-modulated striatal calpain activity in YAC transgenic huntington disease mouse model: impact on NMDA receptor function and toxicity J. Neurosci. 28 2008 12725 12735
73. J. Gafni, and L.M. Ellerby Calpain activation in Huntington's disease J. Neurosci. 22 2002 4842 4849 (Pubitemid 37465599)
74. C. Landles Proteolysis of mutant huntingtin produces an exon 1 fragment that accumulates as an aggregated protein in neuronal nuclei in Huntington disease J. Biol. Chem. 285 2010 8808 8823
75. R.K. Graham Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin Cell 125 2006 1179 1191 (Pubitemid 43866195)
76. J. Gafni Inhibition of calpain cleavage of huntingtin reduces toxicity: accumulation of calpain/caspase fragments in the nucleus J. Biol. Chem. 279 2004 20211 20220 (Pubitemid 38623466)
77. C.L. Wellington Inhibiting caspase cleavage of huntingtin reduces toxicity and aggregate formation in neuronal and nonneuronal cells J. Biol. Chem. 275 2000 19831 19838 (Pubitemid 30441585)
78. M. Chen Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease Nat. Med. 6 2000 797 801 (Pubitemid 30469429)
79. S. Toulmond Neuroprotective effects of M826, a reversible caspase-3 inhibitor, in the rat malonate model of Huntington's disease Br. J. Pharmacol. 141 2004 689 697 (Pubitemid 38453261)
80. Y.K. Jo ARP101, a selective MMP-2 inhibitor, induces autophagy-associated cell death in cancer cells Biochem. Biophys. Res. Commun. 404 2011 1039 1043
81. H.G. Hacker Allosteric modulation of caspases Pharmacol. Ther. 132 2011 180 195
82. I.O. Donkor Calpain inhibitors: a survey of compounds reported in the patent and scientific literature Exp. Opin. Ther. Pat. 21 2011 601 636
83. A. Mikosik Ex vivo measurement of calpain activation in human peripheral blood lymphocytes by detection of immunoreactive products of calpastatin degradation Folia Histochem. Cytobiol. 45 2007 343 347 (Pubitemid 351193608)
84. M.C. Maillard Exploiting differences in caspase-2 and -3 S subsites for selectivity: structure-based design, solid-phase synthesis and in vitro activity of novel substrate-based caspase-2 inhibitors Bioorg. Med. Chem. 19 2011 5833 5851
85. W. Lubisch Benzoylalanine-derived ketoamides carrying vinylbenzyl amino residues: discovery of potent water-soluble calpain inhibitors with oral bioavailability J. Med. Chem. 46 2003 2404 2412 (Pubitemid 36637924)
86. N.O. Carragher Calpain inhibition: a therapeutic strategy targeting multiple disease states Curr. Pharm. Des. 12 2006 615 638
87. M.J. Leyva Identification and evaluation of small molecule pan-caspase inhibitors in Huntington's disease models Chem. Biol. 17 2010 1189 1200
88. S.G. Gray Targeting histone deacetylases for the treatment of Huntington's disease CNS Neurosci. Ther. 16 2010 348 361
89. R. Butler, and G.P. Bates Histone deacetylase inhibitors as therapeutics for polyglutamine disorders Nat. Rev. Neurosci. 7 2006 784 796 (Pubitemid 44435261)
90. A.G. Kazantsev, and L.M. Thompson Therapeutic application of histone deacetylase inhibitors for central nervous system disorders Nat. Rev. Drug Discov. 7 2008 854 868
91. E.A. Thomas Focal nature of neurological disorders necessitates isotype-selective histone deacetylase (HDAC) inhibitors Mol. Neurobiol. 40 2009 33 45
92. A. Bobrowska Hdac6 knock-out increases tubulin acetylation but does not modify disease progression in the R6/2 mouse model of Huntington's disease PLoS ONE 6 2011 e20696
93. C.L. Benn Genetic knock-down of HDAC7 does not ameliorate disease pathogenesis in the R6/2 mouse model of Huntington's disease PLoS ONE 4 2009 e5747
94. L. Moumne Genetic knock-down of Hdac3 does not modify disease-related phenotypes in a mouse model of Huntington's disease PLoS ONE 7 2012 e31080
95. M. Mielcarek SAHA decreases HDAC 2 and 4 levels in vivo and improves molecular phenotypes in the R6/2 mouse model of Huntington's disease PLoS ONE 6 2011 e27746
96. H. Jeong Acetylation targets mutant huntingtin to autophagosomes for degradation Cell 137 2009 60 72
97. X. Cong Mass spectrometric identification of novel lysine acetylation sites in huntingtin Mol. Cell Proteom. 10 2011 111
98. J. Pallos Inhibition of specific HDACs and sirtuins suppresses pathogenesis in a Drosophila model of Huntington's disease Hum. Mol. Genet. 17 2008 3767 3775
99. J.A. Parker Resveratrol rescues mutant polyglutamine cytotoxicity in nematode and mammalian neurons Nat. Genet. 37 2005 349 350
100. H. Jeong Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway Nat. Med. 18 2012 159 165
101. M. Jiang Neuroprotective role of Sirt1 in mammalian models of Huntington's disease through activation of multiple Sirt1 targets Nat. Med. 18 2012 153 158
102. C.H. Arrowsmith Epigenetic protein families: a new frontier for drug discovery Nat. Rev. Drug Discov. 11 2012 384 400
103. R.H. Houtkooper Sirtuins as regulators of metabolism and healthspan Nat. Rev. Mol. Cell Biol. 13 2012 225 238
104. C.T. Aiken Phosphorylation of threonine 3: implications for Huntingtin aggregation and neurotoxicity J. Biol. Chem. 284 2009 29427 29436
105. R.S. Atwal Kinase inhibitors modulate huntingtin cell localization and toxicity Nat. Chem. Biol. 7 2011 453 460
106. L.S. Havel Preferential accumulation of N-terminal mutant huntingtin in the nuclei of striatal neurons is regulated by phosphorylation Hum. Mol. Genet. 20 2011 1424 1437
107. L.M. Thompson IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome J. Cell Biol. 187 2009 1083 1099
108. X. Gu Serines 13 and 16 are critical determinants of full-length human mutant huntingtin induced disease pathogenesis in HD mice Neuron 64 2009 828 840
109. S. Humbert The IGF-1/Akt pathway is neuroprotective in Huntington's disease and involves Huntingtin phosphorylation by Akt Dev. Cell 2 2002 831 837 (Pubitemid 34650078)
110. S.C. Warby Huntingtin phosphorylation on serine 421 is significantly reduced in the striatum and by polyglutamine expansion in vivo Hum. Mol. Genet. 14 2005 1569 1577 (Pubitemid 40823464)
111. M. Metzler Phosphorylation of huntingtin at Ser421 in YAC128 neurons is associated with protection of YAC128 neurons from NMDA-mediated excitotoxicity and is modulated by PP1 and PP2A J. Neurosci. 30 2010 14318 14329
112. E. Colin Huntingtin phosphorylation acts as a molecular switch for anterograde/retrograde transport in neurons EMBO J. 27 2008 2124 2134
113. B. Schilling Huntingtin phosphorylation sites mapped by mass spectrometry. Modulation of cleavage and toxicity J. Biol. Chem. 281 2006 23686 23697 (Pubitemid 44274144)
114. S.L. Anne Phosphorylation of huntingtin by cyclin-dependent kinase 5 is induced by DNA damage and regulates wild-type and mutant huntingtin toxicity in neurons J. Neurosci. 27 2007 7318 7328 (Pubitemid 47037570)
115. S. Luo Cdk5 phosphorylation of huntingtin reduces its cleavage by caspases: implications for mutant huntingtin toxicity J. Cell Biol. 169 2005 647 656 (Pubitemid 41002857)
116. D.M. Virshup, and S. Shenolikar From promiscuity to precision: protein phosphatases get a makeover Mol. Cell 33 2009 537 545
117. V.V. Vintonyak The therapeutic potential of phosphatase inhibitors Curr. Opin. Chem. Biol. 13 2009 272 283
118. M. Voronkov Phosphoprotein phosphatase 2A: a novel druggable target for Alzheimer's disease Fut. Med. Chem. 3 2011 821 833
119. V.V. Vintonyak Using small molecules to target protein phosphatases Bioorg. Med. Chem. 19 2011 2145 2155
120. E.S. Johnson Protein modification by SUMO Annu. Rev. Biochem. 73 2004 355 382 (Pubitemid 39050373)
121. A. Hershko, and A. Ciechanover The ubiquitin system Annu. Rev. Biochem. 67 1998 425 479 (Pubitemid 28411135)
122. S. Subramaniam Rhes, a striatal specific protein, mediates mutant-huntingtin cytotoxicity Science 324 2009 1327 1330
123. S. Subramaniam Rhes, a physiologic regulator of sumoylation, enhances cross-sumoylation between the basic sumoylation enzymes E1 and Ubc9 J. Biol. Chem. 285 2010 20428 20432
124. M. Aghajan Chemical genetics screen for enhancers of rapamycin identifies a specific inhibitor of an SCF family E3 ubiquitin ligase Nat. Biotechnol. 28 2010 738 742
125. V.E. Albrow Development of small molecule inhibitors and probes of human SUMO deconjugating proteases Chem. Biol. 18 2011 722 732
126. J.E. Smotrys, and M.E. Linder Palmitoylation of intracellular signaling proteins: regulation and function Annu. Rev. Biochem. 73 2004 559 587 (Pubitemid 39050380)
127. A. Yanai Palmitoylation of huntingtin by HIP14 is essential for its trafficking and function Nat. Neurosci. 9 2006 824 831
128. F.J. Dekker Small-molecule inhibition of APT1 affects Ras localization and signaling Nat. Chem. Biol. 6 2010 449 456
129. Ramaswamy, S. and Kordower, J.H. Gene therapy for Huntington's disease. Neurobiol. Dis. (in press)
130. S. Meghan, and A. Neil RNA- and DNA-based therapies for Huntington's disease D.C. Lo, R.E. Hughes, Neurobiology of Huntington's Disease: Applications to Drug Discovery 2011
131. D.C. Butler Engineered antibody therapies to counteract mutant huntingtin and related toxic intracellular proteins Prog. Neurobiol. 97 2012 190 204